DepTOR potentially modulate alloreactive immune responses by impairing T effector or regulatory T cell function

• Applicant: Johannes Wedel, Ph.D.
• Subject Area: Immunology
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 268826163

DepTOR is an evolutionarily conserved and first-in-kind cell intrinsic factor that was recently discovered as an mTOR-binding partner that regulates mTOR signaling in cancer cells. As mTOR signaling cascade is important for proinflammatory responses in T cells, in this proposal, we will test this possibility and determine the ability of DepTOR to regulate intracellular signals in the CD4+ T cell and its effects on the CD4+ T effector response(s).Our approach will be systematic and mechanistic to evaluate, first, DepTOR function in the modulation of intracellular signaling networks in CD4+ T cells in vitro, and second, its role in T effector and T regulatory interactions in vivo under homeostatic conditions and in association with allograft rejection. To this end, we already produced transgenic doxycycline-inducible DepTOR and DepTORlox/lox mice. Next to a phenotyping of forced DepTOR overexpression and CD4+ cell- respectively FoxP3+ cell-specific DepTOR knockout mice, we want to investigate the acute and chronic rejection response to allogeneic skin and heart transplantation in the overexpression vs. wildtype vs. specific CD4- and FoxP3-DepTOR knockout conditions. Last but not least we want to combine the transplantation models with immunodeficient Rag2-/-Il2rg-/- recipients with an adoptive cell co-transfer of DepTOR overexpressing respectively wildtype T effectors with DepTOR overexpressing respectively wildtype regulatory T cells to identify the cell specific role of DepTOR in T effector respectively T regulatory interactions in the allogeneic rejection response.Although little is currently known about DepTOR in immunity, we strongly believe to identify DepTOR, for the first time, as a modulator of T cell activation and immunoregulation. Since it is possible to target DepTOR degradation, our results will also have broad clinical and therapeutic implications.All in vitro techniques and in vivo models are routine in our laboratory and our approach provides for cohesiveness between analyses of DepTOR function in CD4+ T cells in vitro and functional studies in vivo.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. David Briscoe